Certain dihydrotriazine derivatives have been explored as antimalarial compositions (Onori et al., Ann. 1st Super Sanita., 1989, 25:659-74). However, they are poorly absorbed and have been shown to be less effective in eliciting cures when administered orally, as compared to injection, to malaria-infected Aotus monkeys. These triazine derivatives must be administered by injection to observe activity comparable to or exceeding other known antimalarial drugs and are poorly tolerated when given by the oral route. (Knight et al., I. Ann. Tropical Med. Parasitol., 1980 74:393-404; Knight et al, IV. Ann. Trop. Med. Parasitol. 1982 76:9-14; U.S. Pat. No. 4,232,022; and U.S. Pat. No. 4,179,562).
Certain other dihydrotriazine derivatives have been explored as antimicrobial or antimalarial compositions. (U.S. Pat. No. 3,723,429)
U.S. Pat. No. 5,322,858 discloses biguanide derivatives, including N1,N5-substituted asymmetrical imidodicarbonimidic diamides, having antimicrobial and antiparasitic activity of various kinds, including antimalarial and antituberculosis activity, and discloses that such compounds provide elevated levels of bioavailability due to their ready absorption when taken orally. While the imidodicarbonimidic diamides exhibited inherent biological activities in claimed therapeutic applications, significant activities of the claimed compounds may arise by virtue of their conversions, in vivo, to the corresponding dihydrotriazine metabolites.
More recently, Jensen, et al., J. Med. Chem. 2001, 44, 3925-3931 reported a series of dihydrofolate reductase inhibitors that were effective as antimalarial agents, and unlike earlier antimalarial agents, were not cross-resistant with their previous counterparts.
In view of the importance of pharmaceutical compounds with these types of biological activity in the treatment of malaria, and other microbial and parasitic-type diseases and afflictions, compounds with enhanced pharmaceutical properties, and their methods of manufacture, are needed. Such improvements may include, for example, one or more of the following: enhanced biological activity, decreased toxicity, improved stability, better patient drug tolerance, increased solubility, in-use cost effectiveness, improved bioavailability, ease of drug administration, simplicity of manufacture, use of more environmentally friendly reagents, reduced environmental impact of co-generated by-products and their related waste disposal issues, and the like.
The compounds, processes for their manufacture, methods of use, and compositions of the present invention are directed to these, as well as other, important needs.